The acute respiratory distress syndrome (ARDS) is most commonly due to severe bacterial infection, including pneumonia. Despite decades of intense study, mortality rates for ARDS are still very high and yet newer therapeutic strategies based on fundamentally novel molecular-pathophysiologic-driven models have not emerged. This PPG application is based on our seminal discovery that a critical mitochondrial-specific lipid, cardiollpin, profoundly produces ARDS-like features when released into the extracellular environment (Nat. Med. 2010). The overall conceptual model underlying this Program is that cardiollpin is a new lipidomic associated molecular pattern encoding bacterial-like molecular signatures that is normally masked by its compartmentalization within the inner mitochondrial membrane of mammalian cells. However, in our preliminary data suggest that in pneumonia models there occur seminal events whereby cardiollpin is exposed into the extracellular environment through its dysregulated biosynthesis (Project 1) or oxidative transmigration (Project 2) from mitochondria in epithelia resulting in severe adverse consequences for immune suppressor activities of myeloid cells (Project 3). Thus, the overall hypothesis is that cardiollpin elicits differential efects on pulmonary homeostasis in ARDS that are cell specific and highly compartmentalized. To execute this Program, we have assembled a team of world-class leaders with complementary expertise to synergistically investigate mechanisms that modulate availability cardiollpin and its role in mitochondrial integrity, epithelial apoptosis, and innate immune function. To evaluate the hypothesis, investigators will employ state-of-art molecular, cell-based, and lipidomic tools that will be translated to complementary in vivo models of lung injury and analysis in human subjects with ARDS. The Program will be supported by highly interactive Cores with expertise in oxidative lipidomics, animal and human repository services, and bioimaging. Execution of these studies will provide a paradigm-changing conceptual model for ARDS pathogenesis that serves as a basis for therapeutic intervention and providing a new and sustained field of scientific inquiry in lung biology.